Introduction
Patients with cancer may receive multiple red blood cell (RBC) transfusions. While it is true that humans have no way to excrete excess iron, the high iron levels should block dietary absorption and the excess iron will eventually be utilized over time.  However, these transfusions lead to iron accumulation that may persist, particularly in the extrahepatic sites, long after patients have completed their cancer therapy leading to long-term exposure to toxic forms of iron and the consequences of this exposure is unknown.1,2 Although iron accumulation based on liver iron concentration (LIC) accurately reflects total body iron, it does not reflect movement of toxic ferrous iron into the heart and endocrine organs. Iron measured by MRI is in the non-reactive ferric state. Transferrin bound non-reactive ferric iron enters cells via the transferrin receptor, a process that is shut off if intracellular iron levels are high. Reactive, ferrous iron is present at very low levels in circulation but increases dramatically when transferrin saturation exceeds 60%, which occurs as soon as erythropoiesis is suppressed by cytotoxic chemotherapy.3 Ferrous iron can enter cells non-physiologically through divalent calcium and zinc transporters that are not regulated by iron. While it is clear from transfusion-dependent anemias that organ toxicity is related to exposure to ferrous iron, the presence and impact of exposure to toxic iron is not clear in pediatric oncology patients.
Toxicities such as endocrine failure and malignant transformation are related to iron overload (IO)4,5 and overlap with treatment-induced late effects observed in cancer survivors.6-8 Considering the existing data that these are reversible or even preventable by treatment of IO in transfusion dependent anemia patients,9,10 it would be reasonable to assume that this would be the case in pediatric oncology patients despite the lack of corresponding data in this population. Organ toxicity from iron is related primarily to the amount of reactive iron in tissue and duration of exposure.11 Due to expected long-term survival of most pediatric cancer patients, mitigation of complications is of increased importance. Since these iron-related complications may take decades to become apparent, appropriately-designed prospective studies to prove causality are not feasible. Based on the known risks of long-term exposure to excess iron from other disorders11 and the current ability to easily monitor and safely remove excess iron12, correction of IO in pediatric cancer patients should be a clinical priority for pediatric survivorship clinics. However, there are many challenging questions regarding when and how to treat the IO that occurs in cancer patients.
The Iron Overload Program at Children’s Hospital Los Angeles (CHLA), which focuses on chronic transfusion dependent anemia and genetic iron overload syndromes, started an oncology Iron Overload Clinic in 2016. The diagnostic and treatment approaches are based on our understanding of principles of iron biology and understanding of the current oncology treatment. We present a retrospective assessment of organ-specific IO in a diverse sample of pediatric oncology patients and discuss the results in the context of the iron toxicity biology.